Our specific goals are to identify drugs that will target Epstein-Barr virus (EBV) latent infections and EBV- associated hematologic cancers and proliferative disorders that occur in the human host. EBV is a herpesvirus that infects approximately 95% of the human population and usually results in the benign, latent infection of memory B lymphocytes for the life of the host. EBV is unique, however, in that latent infection can lead to virus- associated malignancies such as Burkitt's lymphoma (BL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and nasopharyngeal carcinoma (NPC). Understanding EBV latent infection provides insight into the pathogenesis of EBV-associated disease and may lead to targeted therapies to prevent or treat EBV- associated malignancies. Latent membrane protein 2A (LMP2A) is an EBV protein expressed in latently infected B-lymphocytes and detected in EBV-associated malignancies. LMP2A alters and mimics normal B cell signaling pathways induced by the B cell receptor (BCR) to prevent apoptosis and prolong cell survival. LMP2A function is dependent on numerous cellular proteins including the Lyn and Syk protein tyrosine kinases (PTKs), and the Ras/PI3K/Akt pathway. We hypothesize that LMP2A is essential for EBV latency and EBV-associated pathogenesis by altering normal BCR function and activating intracellular pro-survival and anti-apoptotic pathways that block important cellular checkpoints such as Myc-induced apoptosis. Using a novel in vivo murine model of EBV latency developed in our laboratory and a novel in vitro methodology, we will test pharmacological inhibitors of LMP2A-activated proteins. As described in the proposal, many of these inhibitors are currently being tested and are in early stages of human trials for treatment of other diseases unrelated to EBV-associated disease. Promising data using our murine transgenic model would provide important data to justify proposed human studies with EBV-related lymphomas. Finally, other targets may be identified in our proposed research that effectively target LMP2A function. Overall, the studies proposed will test the feasibility of LMP2A signaling inhibition, will determine the most effective agents to inhibit LMP2A signaling activity, will provide a foundation for in vivo drug developmental studies aimed at the eradication of EBV latency as treatment or prevention for EBV-associated malignancies, and may offer therapeutic options for EBV- associated cancers such as EBV-associated Hodgkin lymphoma and NHL. Epstein-Barr virus (EBV) is a herpesvirus that ubiquitously infects the human population resulting usually in the benign, latent infection of white blood cells. However, EBV infection and the resulting latent infection can lead to virus-associated proliferative disorders such as Burkitt's lymphoma and Hodgkin lymphoma. Our specific goals are to identify drugs that target EBV latent infections and EBV-associated lymphomas that occur in the human host by using inhibitors of cell proteins targeted by EBV.